Angiogenesis and vasculogenesis are processes involved in the growth of blood vessels. Angiogenesis is the process by which new blood vessels are formed from extant capillaries, while vasculogenesis involves the growth of vessels deriving from endothelial progenitor cells. Angiogenesis is a complex, combinatorial process that is regulated by a balance between pro- and anti-angiogenic molecules. Angiogenic stimuli (e.g. hypoxia or inflammatory cytokines) result in the induced expression and release of angiogenic growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF). These growth factors stimulate endothelial cells (EC) in the existing vasculature to proliferate and migrate through the tissue to form new endothelialized channels.
Angiogenesis and vasculogenesis, and the factors that regulate these processes, are important in embryonic development, inflammation, and wound healing, and also contribute to pathologic conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis; and chronic inflammatory diseases (see, e.g., U.S. Pat. No. 5,318,957; Yancopoulos et al. (1998) Cell 93:661-4; Folkman et al. (1996) Cell 87;1153-5; and Hanahan et al. (1996) Cell 86:353-64).
Both angiogenesis and vasculogenesis involve the proliferation of endothelial cells. Endothelial cells line the walls of blood vessels; capillaries are comprised almost entirely of endothelial cells. The angiogenic process involves not only increased endothelial cell proliferation, but also comprises a cascade of additional events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane. Vasculogenesis involves recruitment and differentiation of mesenchymal cells into angioblasts, which then differentiate into endothelial cells which then form de novo vessels (see, e.g., Folkman et al. (1996) Cell 87:1153-5).
Inappropriate, or pathological, angiogenesis is involved in the growth of atherosclerotic plaque, diabetic retinopathy, degenerative maculopathy, retrolental fibroplasia, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, and asthma. Furthermore, tumor progression is associated with neovascularization, which provides a mechanism by which nutrients are delivered to the progressively growing tumor tissue.
While the concept of slowing or even halting the progression of cancer by targeting its blood supply was first proposed more than 30 years ago (Folkman, 1971), angiogenesis inhibitors are only now entering the mainstream of cancer therapeutics (Hurwitz et al., 2004). The success of Avastin, a monoclonal antibody raised against Vascular Endothelial Growth Factor (VEGF), in treating colon cancer brings hope for the use of angiogenesis inhibitors for the treatment of other malignancies such as prostate cancer—one of the most common cancers in men (Young, 2002). There is a need in the art for methods of reducing pathological angiogenesis. The present invention addresses this need.
Schuller et al. (1989) Carcinogenesis 10:1753-1755; Maneckjee et al. (1994) Cell Growth Differ. 5:1033-1040; Hong et al. (1995) J. Pharm. Sci. 84:65-70; Schuller et al. (1989) Biochem. Pharmacol. 38:3439-3442; U.S. Pat. No. 5,318,957; Yancopoulos et al. (1998) Cell 93:661-4; Folkman et al. (1996) Cell 87;1153-5; and Hanahan et al. (1996) Cell 86:353-64). Carmeliet et al. (2000) Nature 407:249-257; Folkman (1995) Nat Med 1:27-31; Heeschen et al. (2001) Nat Med 7:833-837; Grando et al. (1995) J Invest Dermatol 105:774-781; Macklin et al. (1998) Pharmacol Exp Ther 287:435-439; Wessler et al. (1999) Clin Exp Pharmacol Physiol 26:198-205; Kawashima et al. (1989) Neurosci Lett 104:336-339; Kawashima et al. (1990) Neurosci Lett 119:156-158; Kureishi et al. (2000) Nat Med 6:1004-1010; Jang et al. (2000) Circulation 102:1414-1419; Couffinhal et al. (1998) Am J Pathol 152:1667-1679; Lagasse and Weissman (1996) J Immunol Methods 197:139-150; and Villablanca (1998 J Appl Physiol 84:2089-2098.